泛素连接酶
CREB结合蛋白
蛋白酶体
细胞生物学
乙酰转移酶
转录因子
计算生物学
泛素
蛋白质水解
增强子
化学
生物化学
乙酰化
生物
酶
奶油
基因
作者
Iván Cheng-Sánchez,Katherine A. Gosselé,Leonardo Palaferri,Mariia S. Kirillova,Cristina Nevado
标识
DOI:10.1021/acsmedchemlett.3c00490
摘要
Proteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that simultaneously bind an E3 ligase and a protein of interest, inducing degradation of the latter via the ubiquitin-proteasome system. Here we present the development of degraders targeting CREB-binding protein (CBP) and E1A-associated protein (EP300)-two homologous multidomain enzymes crucial for enhancer-mediated transcription. Our PROTAC campaign focused on CPI-1612, a reported inhibitor of the histone acetyltransferase (HAT) domain of these two proteins. A novel asymmetric synthesis of this ligand was devised, while PROTAC-SAR was explored by measuring degradation, target engagement, and ternary complex formation in cellulo. Our study demonstrates that engagement of Cereblon (CRBN) and a sufficiently long linker between the E3 and CBP/EP300 binders (≥21 atoms) are required for PROTAC-mediated degradation using CPI-1612 resulting in a new active PROTAC dCE-1. Lessons learned from this campaign, particularly the importance of cell-based assays to understand the reasons underlying PROTAC performance, are likely applicable to other targets to assist the development of degraders.
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